Sporadic inclusion body myositis--diagnosis, pathogenesis and therapeutic strategies.

Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical phenotype of slow-onset weakness and atrophy, affecting proximal and distal limb muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated fibers, vacuolar degeneration, and accumulation of amyloid-related proteins. The cause of sIBM is unclear, but two processes-one autoimmune and the other degenerative-appear to occur in parallel. In contrast to dystrophies, in sIBM the autoinvasive CD8(+) T cells are cytotoxic and antigen-driven, invading muscle fibers expressing major histocompatibility complex class I antigen and costimulatory molecules. The concurrent degenerative features include vacuolization, filamentous inclusions and intracellular accumulations of amyloid-beta-related molecules. Although viruses have not been amplified from the muscle fibers, at least 12 cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor. Emerging data imply that continuous upregulation of cytokines and major histocompatibility complex class I on the muscle fibers causes an endoplasmic reticulum stress response, resulting in intracellular accumulation of misfolded glycoproteins and activation of the transcription factor NFkappaB, leading to further cytokine activation. In spite of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to immunotherapies. New therapies using monoclonal antibodies against lymphocyte signaling pathways might prove helpful in arresting disease progression.